The clinical research program described in this report is dedicated to the translation of basic research findings into clinical trials of novel therapies for inflammatory bowel diseases (IBD). In addition, it is structured so as to use basic research methods to define the immune and genetic mechanisms underlying IBD in a variety of settings. This year's research accomplishments include the continuing enrollment of our bench-to-bedside project with the University of Maryland and Yale University, and the initiation of a protocol studying the safety and efficacy of allogenic bone marrow derived mesenchymal stromal cell infusions for the treatment of IBD. We also collaborated successfully with investigators in Dr. Polly Matzinger's laboratory in studies of CVID and Dr. Phil McCoy's laboratory in studies of autoimmunity. We were awarded $140,000 by the Bench-to-Bedside Committee to collaborate with the University of Maryland Medical System Department of Gastroenterology and Hepatology to study the mechanisms underlying the response or non-response to anti-TNF therapy. We have successfully started the study with them and are currently enrolling patients. We also have expanded the project to include the Yale Digestive Diseases group. This project is nearing completion as we are looking to enroll our target of 20 patients. We continue to conduct clinical studies patients with CVID. This includes on-going studies of patients with CVID and GI disorders characterized by enteropathy and malabsorption. In prior studies of these patients we established that the GI syndrome in CVID is driven by cells producing IFN-gamma. We are therefore in the early stages of collaboration with pharmaceutical companies with experimental agents that target this cytokine. As mentioned above, we collaborated with investigators in Dr. Polly Matzinger's Laboratory in studies of CVID; these studies included microarray analyses of biopsy tissue of CVID patients with enteropathy that showed that CVID enteropathy is characterized by upregulation of genes related to type 1 interferon. We are planning to pursue this observation in collaborative studies with researchers at Oregon State University to more clearly define the genes and cells involved in this abnormality. In collaboration with Dr. Harry Malech and his colleagues we continue to conduct studies of colitis occurring in patient CGD. These studies include the evaluation of cytokine production in the inflamed mucosa of CGD patients with the goal of identifying unique cytokine profiles underlying this disease manifestation.